Generic Name

Xyrem

Mechanism

Sodium oxybate is a short‑acting centrally acting neurotoxin that:
• Binds preferentially to GABAB receptors (primary site of action) and, at higher concentrations, to GABAA receptors, producing a net hyperpolarizing effect on neurons.
• Inhibits orexin (hypocretin) neurons in the lateral hypothalamus, thereby reducing sudden muscle tone loss (cataplexy) and improving sleep architecture.
• Modulates circadian rhythm by increasing slow‑wave (deep) sleep, reducing awakenings, and normalizing 24‑hour sleep patterns.

Pharmacokinetics

• Absorption: Rapid oral absorption with peak plasma concentrations at ~1 h (first dose) and ~2 h (second dose). Food delays absorption: a high‑fat meal increases Tmax and reduces peak concentration by ~30 %.
• Distribution: Highly lipophilic; crosses the blood‑brain barrier readily. Low plasma protein binding (~30 %).
• Metabolism: Minimal hepatic metabolism via non‑enzymatic hydrolysis to succinic acid. Primarily eliminated unchanged in urine.
• Elimination: Half‑life ≈ 1.5 h. Due to ultrashort action, twice‑daily dosing is required.
• Drug Interactions: Potentiated effects with CNS depressants (benzodiazepines, opioids, alcohol). CYP inhibitors/inducers have negligible influence.

Indications

• Narcolepsy with cataplexy or excessive daytime sleepiness *and* disrupted nighttime sleep.
• Refractory cataplexy when other first‑line therapies fail.
• Off‑label use: insomnia secondary to narcolepsy, restless leg syndrome (rare).

Contraindications

• Contraindications: Severe hepatic impairment, known hypersensitivity to GHB, pregnancy, lactation (data insufficient), uncontrolled seizures, and patients with a history of drug dependence (risk of misuse).
• Warnings:
• Abuse Potential: Schedule‑IV classification; monitor for signs of dependence.
• Respiratory Depression: Especially when combined with other CNS depressants; avoid in patients with severe respiratory disorders (COPD, sleep apnea).
• Seizure Risk: Increased seizure frequency in patients with a history of seizures; avoid in status epilepticus.
• CNS Depression: Monitor for hypotension, dizziness, or impaired cognition after initiation.

Dosing

Key points:
• Administer in a controlled environment (clinical setting) initially.
• Total nightly dose ≤ 5.6 g (5.625 g when using 250 mL water).
• Re‑titration to a minimum clinical effective dose after at least one week to reduce risk of withdrawal.

Monitoring

• Baseline: CBC, CMP, fasting lipid profile, liver function tests, 12‑lead ECG if cardiac history.
• Follow‑up:
• Sleep diary (time to onset of sleep, awakenings, total sleep time).
• Cataplexy episode frequency (self‑reported).
• Adverse effect questionnaire.
• Safety:
• Observe for signs of abuse (increased titration, “bunching” of doses).
• Respiratory rate and SpO₂ if COPD or sleep apnea.
• Blood pressure monitoring post‑dose for first 4–6 h.

Clinical Pearls

• “Bunching” Prevention: Instruct patients to avoid dosing two or more doses back‑to‑back; schedule at least 4 h apart to prevent abuse potential and respiratory depression.
• First‑Night Supervision: Initiate therapy in a monitored setting—a 24‑h observation period reduces early withdrawal crises.
• Dose Ceiling: Max nightly dose is 5.6 g. Exceeding this increases respiratory risk without additional benefit.
• Renal vs. Hepatic: Renal impairment does not necessitate dose adjustment; hepatic impairment should prompt cautious use or consider alternative narcolepsy agents.
• Discontinuation Strategy: Taper 1.875 g every 3–5 days to avoid withdrawal; hold if any dose elicits severe hypotension or respiratory compromise.
• Patient Education: Emphasize strict adherence to dosing schedule, discourage alcohol, and warn of sudden withdrawal symptoms—use a supportive hand‑out summarizing key safety points.

Quick Reference: Xyrem is potent, short‑acting, and has a narrow therapeutic index; meticulous titration and monitoring are essential for safe, effective use in narcolepsy management.